Systems and methods for therapy titration in heart failure

ABSTRACT

Systems and methods for treating a medical condition such as worsening heart failure (WHF) are described. A medical system may sense one or more physiological signals, and generate from the sensed physiological signals a signal metric trend indicating a progression of heart failure. A detector may detect a physiological event leading to WHF. A therapy control circuit may generate a therapy titration protocol using the generated signal metric trend. The therapy titration protocol includes a temporal profile of therapy dosage relative to a target dosage. The therapy control circuit may adjust the target dosage based on patient response. Therapies may be administered by a clinician or automatically delivered to the patient according to the therapy titration protocol.

CLAIM OF PRIORITY

This application is a continuation of U.S. Application Serial No.16/111,019, filed Aug. 23, 2018, which claims the benefit of priorityunder 35 U.S.C. § 119(e) of U.S. Provisional Pat. Application SerialNumber 62/561,004, filed on Sep. 20, 2017, which are herein incorporatedby reference in their entireties.

TECHNICAL FIELD

This document relates generally to medical systems, and moreparticularly, to systems, devices and methods for titrating therapydosage in heart failure.

BACKGROUND

Congestive heart failure (CHF or HF) is a major health problem andaffects many people in the United States alone. CHF patients may haveenlarged heart with weakened cardiac muscles, resulting in poor cardiacoutput of blood. Although CHF is usually a chronic condition, it mayoccur suddenly. It may affect the left heart, right heart or both sidesof the heart. If CHF affects the left ventricle, signals that controlthe left ventricular contraction are delayed, and the left and rightventricles do not contract simultaneously. Non-simultaneous contractionsof the left and right ventricles may decrease the pumping efficiency ofthe heart.

In many CHF patients, elevated pulmonary vascular pressures may causefluid accumulation in the lungs over time. The fluid accumulation mayprecede or coincide with worsening heart failure (WHF), such as a HFdecompensation event. WHF may be characterized by pulmonary orperipheral edema, reduced cardiac output, and symptoms such as fatigue,shortness of breath, and the like.

CHF may be treated by medical therapy, or by an implantable medicaldevice (IMD) that may provide electrostimulation therapy. An IMD canmonitor patient health condition such as progression of CHF, and deliverelectrostimulation to restore or improve cardiac performance, or torectify cardiac arrhythmias. One example of electrostimulation therapyis resynchronization therapy (CRT), which involves electrostimulation ofboth left and right ventricles to promote synchronous pumping betweenboth ventricles. Medical therapy for treating CHF may involve one ormore medications, such as diuretics to reduce edema,Angiotensin-converting enzyme (ACE) inhibitors or Angiotensin IIreceptor blockers to promote vasodilation and therefore improve bloodflow and decrease heart workload, inotropes to improve heart pumpingfunction and maintain blood pressure, or digoxin to increase thestrength of myocardial contraction and to slow the heartbeat, amongother medications. Device therapy and medical therapy may be titrated toreduce morbidity and mortality in CHF.

OVERVIEW

Frequent monitoring of CHF patients and timely detection of eventsindicative of WHF may help reduce healthcare cost associated with HFhospitalization. Identification of patient at an elevated risk ofdeveloping WHF may help ensure timely treatment, improve the prognosisand patient outcome, and avoid unnecessary medical interventions andsave the overall cost.

Ambulatory medical devices (AMDs) may be used for monitoring HF patientand detecting WHF events. Examples of such ambulatory medical devicesmay include implantable medical devices (IMD), subcutaneous medicaldevices, wearable medical devices or other external medical devices. AnAMD may include sensors to sense physiological signals. An AMD maydetect a WHF event based on a temporal change in a physiological signal,or a temporal change in measurements of composite metric derived from anumber of physiological signals. When the physiological signal or thecomposite metric crosses respective detection thresholds, an alert maybe generated to warn a clinician of an on-going or future WHF event. TheAMD can deliver therapy such as electrostimulation or administermedications to target tissues or organs, automatically or with aclinician intervention, to restore or improve patient cardiac function.

Timely titration of HF therapies, including electrostimulation therapyor medications, to accommodate changes in patient HF status andcomorbidities is important in HF patient management. However, therapytitration can be challenging, partly because HF patients frequently havemultiple co-morbidities, need to take numerous medications, and oftenmove between acute and primary health-care sectors. Lack of a clear,patient-specific titration plan, along with patient adherence issues dueto the changing medication regimen, and inefficient communication ofmedication plans between acute and primary care, many affect therapytitration. Additionally, organizing frequent clinic visits to evaluatepatient therapy responses can be practically difficult for somepatients. As a result, dosages are often not optimized in clinicalpractice. The present inventors have recognized there remains a need fortechnological solutions that may improve HF therapy titration for betterpatient outcome. In particular, the present inventors have recognizedthat the physiological signals or composite metric measurements, whichare used for detecting events leading to WHF, may be used for titratingHF therapy. The individualized therapies or interventions tailored tospecific patient conditions based on the physiological signals orcomposite metric requires little to no additional cost or systemcomplexity.

Embodiments of the present subject matter provide systems, devices, andmethods for adjusting therapy dosage for treating a medical conditionsuch as WHF. A medical system may sense one or more physiologicalsignals, and generate from the sensed physiological signals a signalmetric trend indicating a progression of a physiological condition suchas WHF. An event detector may detect a physiological event leading toWHF. A therapy control circuit may generate a therapy titration protocolusing the signal metric trend. The therapy titration protocol includes atemporal profile of therapy dosage relative to a target dosage.Therapies may be administered by a clinician or automatically deliveredto the patient according to the therapy titration protocol.

Example 1 is a system for adjusting a therapy dosage in a patient. Thesystem comprises a receiver circuit configured to receive one or morephysiological signals, a physiological event detector circuit configuredto generate, from the sensed one or more physiological signals, a signalmetric trend indicating a progression of a physiological condition, andto detect a physiological event using the generated signal metric trend,and a therapy control circuit that is coupled to the physiological eventdetector circuit and configured to generate a therapy titration protocolusing the generated signal metric trend. The therapy titration protocolmay include a temporal profile of therapy dosage relative to a targetdosage.

In Example 2, the subject matter of Example 1 optionally includes atherapy delivery unit that may initiate or adjust a therapy according tothe therapy titration protocol in response to the detection of thephysiological event.

In Example 3, the subject matter of any one or more of Examples 1-2optionally includes the physiological event detector circuit that maydetect a worsening heart failure (WHF) event. The therapy controlcircuit may generate a heart failure therapy titration protocol usingthe generated signal metric trend.

In Example 4, the subject matter of Example 3 optionally includes theheart failure therapy titration protocol that may include a temporalprofile of drug dosage relative to a target drug dosage for treating thedetected WHF.

In Example 5, the subject matter of any one or more of Examples 1-4optionally includes the therapy control circuit that may up-titrate thetherapy dosage when the generated signal metric trend indicates asustained worsening of the physiological condition.

In Example 6, the subject matter of Example 5 optionally includes thetherapy control circuit that may up-titrate the therapy dosage inresponse to the generated signal metric trend exceeding a physiologicalevent onset threshold and indicating an increase trend.

In Example 7, the subject matter of any one or more of Examples 1-6optionally includes the therapy control circuit that may down-titratethe therapy dosage when the generated signal metric trend indicates lackof a sustained worsening of the physiological condition.

In Example 8, the subject matter of Example 7 optionally includes thetherapy control circuit that may down-titrate the therapy dosage inresponse to the generated signal metric trend falling below a specificthreshold and indicating a decrease trend.

In Example 9, the subject matter of any one or more of Examples 1-8optionally includes the temporal profile of therapy dosage that mayinclude a stepwise up-titration or a stepwise down-titration of thetherapy dosage.

In Example 10, the subject matter of any one or more of Examples 1-9optionally includes the therapy control circuit that may adjust thetarget dosage using a comparison of the temporal profile of therapydosage and the target dosage.

In Example 11, the subject matter of Example 10 optionally includes thetherapy control circuit that may increase the target dosage when thetemporal profile of therapy dosage is above the target dosage for afirst time period.

In Example 12, the subject matter of Example 11 optionally includes thetherapy control circuit that may increase the target dosage to a levelcorresponding to a lowest therapy dosage achieved during the first timeperiod.

In Example 13, the subject matter of Example 10 optionally includes thetherapy control circuit that may down-titrate the therapy dosage to alevel lower than the target dosage, evaluate patient response to thedown-titrated therapy dosage over a second time period, and decrease thetarget dosage to a level corresponding to the down-titrated therapydosage if the evaluated patient response indicates no worsening of thephysiological condition during the second time period.

In Example 14, the subject matter of Example 13 optionally includes thepatient response that may include a signal metric trend corresponding tothe down-titrated therapy dosage. The therapy control circuit maydecrease the target dosage if the signal metric trend is within aspecific range indicating no worsening of the physiological conditionduring the second time period.

In Example 15, the subject matter of any one or more of Examples 1-14optionally includes the therapy titration protocol that may include aset of instructions for adjusting patient therapy under specificconditions.

Example 16 is a method for adjusting a therapy dosage in a patient usinga medical system. The method comprises steps of: receiving one or morephysiological signals via a receiver circuit; generating, via aphysiological event detector circuit, from the sensed one or morephysiological signals a signal metric trend indicating a progression ofa physiological condition; detecting a physiological event using thegenerated signal metric trend via the physiological event detectorcircuit; and generating a therapy titration protocol using the generatedsignal metric trend via the therapy control circuit, the therapytitration protocol that may include a temporal profile of therapy dosagerelative to a target dosage.

In Example 17, the subject matter of Example 16 optionally includesinitiating or adjusting a therapy according to the therapy titrationprotocol in response to the detection of the physiological event.

In Example 18, the subject matter of Example 16 optionally includesdetecting the physiological event that may include detecting a worseningheart failure (WHF) event, and generating the therapy titration protocolthat may include generating a heart failure therapy titration protocolusing the generated signal metric trend.

In Example 19, the subject matter of Example 16 optionally includesgenerating a therapy titration protocol that may include one or more of:up-titrating the therapy dosage in response to the generated signalmetric trend exceeding a physiological event onset threshold andindicating an increase trend; or down-titrating the therapy dosage inresponse to the generated signal metric trend falling below a specificthreshold and indicating a decrease trend.

In Example 20, the subject matter of Example 16 optionally includes thetemporal profile of therapy dosage that may include a stepwiseup-titration or a stepwise down-titration of the therapy dosage.

In Example 21, the subject matter of Example 16 optionally includesadjusting the target dosage using a comparison of the temporal profileof therapy dosage and the target dosage.

In Example 22, the subject matter of Example 21 optionally includesadjusting the target dosage that may include, when the temporal profileof therapy dosage is above the target dosage for a first time period,increasing the target dosage to a level corresponding to a lowesttherapy dosage achieved during the first time period.

In Example 23, the subject matter of Example 21 optionally includesadjusting the target dosage that may include: down-titrating the therapydosage to a level lower than the target dosage; evaluating patientresponse to the down-titrated therapy dosage over a second time period;and when the evaluated patient response indicates no worsening of thephysiological condition during the second time period, decreasing thetarget dosage to a level corresponding to the down-titrated therapydosage.

The systems, devices, and methods discussed in this document may improvethe technology of therapy titration in patients with an AMD. Atechnological challenge in HF patient management is timely andindividualized therapy titration based on frequent and effective patientmonitoring. Continuous patient monitoring via the AMD allows for timelydetection of changes in HF status and development of comorbidities. Inaddition to conventional ambulatory patient monitoring and medicaldiagnostic functionality (e.g., detecting a target physiological eventsuch as WHF), the embodiments discussed herein further uses thephysiological signals or composite metric measurements to tailor therapyaccording to an individualized therapy titration protocol. The therapytitration protocol determined based on the changes in physiologicalsignals or composite metric measurements offers the advantage ofindividualized therapy tailored to specific patient conditions, whichmay lead to better treatment and patient management. For example, fewerunnecessary medical interventions, such as drugs, procedures, or devicetherapies, may be scheduled, prescribed, or provided to such patients.As a result, overall system cost savings may be realized. Additionally,the advantages of individualized dosage titration may come with littleto no additional cost or system complexity, at least because thephysiological signals or composite metric measurements are also usedalso for producing HF diagnostics.

The device-based therapy titration as discussed in this document mayalso improve the functionality of a patient management system or device.In some cases, improved therapy titration may be achieved without amodification of the hardware of an existing patient management system oran AMD. Memory usage may be more efficient by storing the therapytitration protocol that is clinically more relevant to patientmanagement strategies. Storage of the therapy titration protocolrequires limited memory storage and transmission bandwidth. A system ora device that generates and stores the therapy titration protocol maynot only improve therapy efficacy and patient outcome, but may alsoreduce unnecessary device therapies, and extend battery life and AMDlongevity.

Although the discussion in this document focuses therapy titration forWHF detected by AMDs, this is meant only by way of example and notlimitation. It is within the contemplation of the inventors, and withinthe scope of this document, that the systems, devices, and methodsdiscussed herein may also be used to detect, and alert occurrence of,cardiac arrhythmias, syncope, pulmonary congestion, respiratory disease,or renal dysfunctions, among other medical conditions. Additionally,although systems and methods are described as being operated orexercised by clinicians, the entire discussion herein applies equally toorganizations, including hospitals, clinics, and laboratories, and otherindividuals or interests, such as researchers, scientists, universities,and governmental agencies, seeking access to the patient data.

This Overview is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects of the disclosure will be apparent to persons skilled in the artupon reading and understanding the following detailed description andviewing the drawings that form a part thereof, each of which are not tobe taken in a limiting sense. The scope of the present disclosure isdefined by the appended claims and their legal equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments are illustrated by way of example in the figures ofthe accompanying drawings. Such embodiments are demonstrative and notintended to be exhaustive or exclusive embodiments of the presentsubject matter.

FIG. 1 illustrates generally an example of a patient management systemand portions of an environment in which the system may operate.

FIG. 2 illustrates generally an example of a patient management systemto detect a target physiological event such as worsening heart failure(WHF), and initiate or titrate a therapy.

FIG. 3 illustrates generally an example of a therapy titration system togenerate a therapy titration protocol for treating a medical condition.

FIGS. 4A-B illustrate examples of a therapy titration protocoldetermined using a signal metric trend and a target dosage.

FIGS. 5A-B illustrate examples of target dosage adjustment using acomparison of a temporal profile of therapy dosage and a target dosage.

FIG. 6 illustrates generally an example of a method for adjusting atherapy in a patient.

FIG. 7 illustrates generally an example of a method for generating atherapy dosage profile to guide treatment of a medical condition.

FIG. 8 illustrates generally a block diagram of an example machine uponwhich any one or more of the techniques (e.g., methodologies) discussedherein may perform.

DETAILED DESCRIPTION

Disclosed herein are systems, devices, and methods for adjusting therapydosage for treating a medical condition, such as worsening heart failure(WHF). A medical system may receive one or more physiological signals,and generate from the received physiological signals a signal metrictrend indicating a progression of a physiological condition. A detectormay detect a physiological event such as a WHF event. A therapy controlcircuit may use the generated signal metric trend to generate a therapytitration protocol that includes a temporal profile of therapy dosagerelative to a target dosage. Therapies may be administered by aclinician or automatically delivered to the patient according to thetherapy titration protocol.

FIG. 1 illustrates generally an example of a patient management system100 and portions of an environment in which the system 100 may operate.The patient management system 100 may perform a range of activities,including remote patient monitoring, diagnosis of a disease condition,and providing information about therapy titration to rectify the diseasecondition and improve patient outcome. Such activities can be performedproximal to a patient, such as in the patient’s home or office, througha centralized server, such as in a hospital, clinic or physician’soffice, or through a remote workstation, such as a secure wirelessmobile computing device.

The patient management system 100 may include an ambulatory system 105associated with a patient 102, an external system 125, and a telemetrylink 115 providing for communication between the ambulatory system 105and the external system 125.

The ambulatory system 105 may include an ambulatory medical device (AMD)110. In an example, the AMD 110 may be an implantable devicesubcutaneously implanted in a chest, abdomen, or other parts of thepatient 102. Examples of the implantable device may include, but are notlimited to, pacemakers, pacemaker/defibrillators, cardiacresynchronization therapy (CRT) devices, cardiac remodeling controltherapy (RCT) devices, neuromodulators, drug delivery devices,biological therapy devices, diagnostic devices such as cardiac monitorsor loop recorders, or patient monitors, among others. The AMD 110alternatively or additionally may include a subcutaneous medical devicesuch as a subcutaneous monitor or diagnostic device, external monitoringor therapeutic medical devices such as automatic external defibrillators(AEDs) or Holter monitors, or wearable medical devices such aspatch-based devices, smart watches, or smart accessories.

By way of example, the AMD 110 may be coupled to a lead system 108. Thelead system 108 may include one or more transvenously, subcutaneously,or non-invasively placed leads or catheters. Each lead or catheter mayinclude one or more electrodes. The arrangements and uses of the leadsystem 108 and the associated electrodes may be determined using thepatient need and the capability of the AMD 110. The associatedelectrodes on the lead system 108 may be positioned at the patient’sthorax or abdomen to sense a physiological signal indicative of cardiacactivity, or physiological responses to diagnostic or therapeuticstimulations to a target tissue. By way of example and not limitation,and as illustrated in FIG. 1 , the lead system 108 may be surgicallyinserted into, or positioned on the surface of, a heart 101. Theelectrodes on the lead system 108 may be positioned on a portion of aheart 101, such as a right atrium (RA), a right ventricle (RV), a leftatrium (LA), or a left ventricle (LV), or any tissue between or near theheart portions. In some examples, the lead system 108 and the associatedelectrodes may alternatively be positioned on other parts of the body tosense a physiological signal containing information about patient heartrate or pulse rate. In an example, the ambulatory system 105 may includeone or more leadless sensors not being tethered to the AMD 110 via thelead system 108. The leadless ambulatory sensors may be configured tosense a physiological signal and wirelessly communicate with the AMD110.

The AMD 110 may be configured as a monitoring and diagnostic device. TheAMD 110 may include a hermetically sealed can that houses one or more ofa sensing circuit, a control circuit, a communication circuit, and abattery, among other components. The sensing circuit may sense aphysiological signal, such as by using a physiological sensor or theelectrodes associated with the lead system 108. Examples of thephysiological signal may include one or more of electrocardiogram,intracardiac electrogram, arrhythmia, heart rate, heart ratevariability, intrathoracic impedance, intracardiac impedance, arterialpressure, pulmonary artery pressure, left atrial pressure, rightventricular (RV) pressure, left ventricular (LV) coronary pressure,coronary blood temperature, blood oxygen saturation, one or more heartsounds, intracardiac acceleration, physical activity or exertion level,physiological response to activity, posture, respiration rate, tidalvolume, respiratory sounds, body weight, or body temperature.

In an example, the AMD 110 may include a therapy control unit 160 forautomatically adjust therapy for treating a medical condition. Examplesof the medical condition include cardiac arrhythmias, worsening of achronic medical condition, such as worsening heart failure (WHF). Thetherapy control unit 160 may detect an event leading to the medicalcondition using a signal metric trend generated from one or morephysiological signal. The therapy control unit 160 may use the signalmetric trend to generate a therapy titration protocol that includes atemporal profile of therapy dosage relative to a target dosage. Thetarget dosage may be adjusted periodically or triggered by an event,based on patient responses. A therapy delivery unit may deliver atherapy according to the therapy titration protocol in response to thedetection of the medical condition. In an example, the titrationprotocol includes a temporal profile of HF drug dosage relative to atarget dosage of the HF drug for treating the detected WHF. Examples ofthe HF drug may include diuretics, ACE inhibitors or Angiotensin IIreceptor blockers, inotropes, or digoxin, among other medications. Inanother example, the titration protocol includes adjustment of anelectrostimulation therapy, such as stimulation site, stimulation mode,or timing and energy of the stimulation, among others.

The external system 125 may include a dedicated hardware/software systemsuch as a programmer, a remote server-based patient management system,or alternatively a system defined predominantly by software running on astandard personal computer. The external system 125 may manage thepatient 102 through the AMD 110 connected to the external system 125 viaa communication link 115. This may include, for example, programming theAMD 110 to perform one or more of acquiring physiological data,performing at least one self-diagnostic test (such as for a deviceoperational status), analyzing the physiological data to detect amedical condition, or optionally delivering or adjusting a therapy tothe patient 102. Additionally, the external system 125 may receivedevice data from the AMD 110 via the communication link 115. Examples ofthe device data received by the external system 125 may includereal-time or stored physiological data from the patient 102, diagnosticdata such as events of WHF, responses to therapies delivered to thepatient 102, or device operational status of the AMD 110 (e.g., batterystatus and lead impedance). The telemetry link 115 may be an inductivetelemetry link, a capacitive telemetry link, or a radio-frequency (RF)telemetry link, or wireless telemetry based on, for example, “strong”Bluetooth or IEEE 802.11 wireless fidelity “WiFi” interfacing standards.Other configurations and combinations of patient data source interfacingare possible.

By way of example and not limitation, the external system 125 mayinclude an external device 120 in proximity of the AMD 110, and a remotedevice 124 in a location relatively distant from the AMD 110 incommunication with the external device 120 via a telecommunicationnetwork 122. Examples of the external device 120 may include aprogrammer device.

The remote device 124 may be configured to evaluate collected patientdata and provide alert notifications, among other possible functions. Inan example, the remote device 124 may include a centralized serveracting as a central hub for collected patient data storage and analysis.The server may be configured as a uni-, multi- or distributed computingand processing system. The remote device 124 may receive patient datafrom multiple patients including, for example, the patient 102. Thepatient data may be collected by the AMD 110, among other dataacquisition sensors or devices associated with the patient 102. Theserver may include a memory device to store the patient data in apatient database. The server may include an alert analyzer circuit toevaluate the collected patient data to determine if specific alertcondition is satisfied. Satisfaction of the alert condition may triggera generation of alert notifications. In some examples, the alertconditions alternatively or additionally may be evaluated by the AMD110. By way of example, alert notifications may include a Web pageupdate, phone or pager call, E-mail, SMS, text or “Instant” message, aswell as a message to the patient and a simultaneous direct notificationto emergency services and to the clinician. Other alert notificationsare possible.

The remote device 124 may additionally include one or more locallyconfigured clients or remote clients securely connected over the network122 to the server. Examples of the clients may include personaldesktops, notebook computers, mobile devices, or other computingdevices. System users, such as clinicians or other qualified medicalspecialists, may use the clients to securely access stored patient dataassembled in the database in the server, and to select and prioritizepatients and alerts for health care provisioning.

The network 122 may provide wired or wireless interconnectivity. In anexample, the network 122 may be based on the Transmission ControlProtocol/Internet Protocol (TCP/IP) network communication specification,although other types or combinations of networking implementations arepossible. Similarly, other network topologies and arrangements arepossible.

One or more of the external device 120 or the remote device 124 mayoutput the detected medical events to a system user such as the patientor a clinician, or to a process including, for example, an instance of acomputer program executable in a microprocessor. In an example, theprocess may include an automated generation of recommendations forinitiating or titrating a medical therapy or an electrostimulationtherapy. In an example, the external device 120 or the remote device 124may include a respective display unit for displaying the physiologicalsignals, the signal metric trend, or the therapy titration protocol,among other intermediate analyses and computations. Alerts, alarms,emergency calls, or other forms of warnings to signal the detectedmedical event may also be generated.

Portions of the AMD 110 or the external system 125 may be implementedusing hardware, software, firmware, or combinations thereof. Portions ofthe AMD 110 or the external system 125 may be implemented using anapplication-specific circuit that may be constructed or configured toperform one or more particular functions, or may be implemented using ageneral-purpose circuit that may be programmed or otherwise configuredto perform one or more particular functions. Such a general-purposecircuit may include a microprocessor or a portion thereof, amicrocontroller or a portion thereof, or a programmable logic circuit, amemory circuit, a network interface, and various components forinterconnecting these components. For example, a “comparator” mayinclude, among other things, an electronic circuit comparator that maybe constructed to perform the specific function of a comparison betweentwo signals or the comparator may be implemented as a portion of ageneral-purpose circuit that may be driven by a code instructing aportion of the general-purpose circuit to perform a comparison betweenthe two signals.

FIG. 2 illustrates generally an example of a patient management system200 configured to detect a target physiological event, such as worseningheart failure (WHF), and initiate or titrate a therapy. The patientmanagement system 200 may include one or more of a receiver circuit 210,a physiological event detector circuit 220, a therapy control circuit230, a user interface 240, and an optional therapy unit 250 fordelivering a therapy to treat a disease or to alleviate a medicalcondition.

At least a portion of the patient management system 200 may beimplemented in the AMD 110, the external system 125 such as one or moreof the external device 120 or the remote device 124, or distributedbetween the AMD 110 and the external system 125. In an example, thereceiver circuit 210, the physiological event detector circuit 220, andthe therapy unit 250 may be implemented in an AMD. In an example, thetherapy control circuit 230 and the user interface 240 may beimplemented in the external system 125. The external system 125 maydetermine a therapy titration protocol and present it to a user such asa clinician. Additionally or alternatively, the external system 125 mayprogram the AMD 110 via the communication link 115 according to thetherapy titration protocol, and the AMD 110 may deliver a devicetherapy. In another example, the therapy titration protocol may includea drug dosage profile, and the external system 125 may program a drugdelivery system, such as a drug infusion pump, to administer themedication according to the therapy titration protocol automatically orwith clinician intervention.

The receiver circuit 210 may receive one or more physiological signalsfrom a patient. In an example, the receiver circuit 210 may be coupledto a sensor circuit that includes a sense amplifier circuit to sense oneor more physiological signals from a patient via one or moreimplantable, wearable, or otherwise ambulatory sensors or electrodesassociated with the patient. The sensors may be incorporated into, orotherwise associated with an ambulatory device such as the AMD 110.Examples of the physiological signals may include surfaceelectrocardiography (ECG) sensed from electrodes placed on the bodysurface, subcutaneous ECG sensed from electrodes placed under the skin,intracardiac electrogram (EGM) sensed from the one or more electrodes onthe lead system 108, thoracic or cardiac impedance signal, arterialpressure signal, pulmonary artery pressure signal, left atrial pressuresignal, RV pressure signal, LV coronary pressure signal, coronary bloodtemperature signal, blood oxygen saturation signal, heart sound signalsuch as sensed by an ambulatory accelerometer or acoustic sensors,physiological response to activity, apnea hypopnea index, one or morerespiration signals such as a respiration rate signal or a tidal volumesignal, brain natriuretic peptide (BNP), blood panel, sodium andpotassium levels, glucose level and other biomarkers and bio-chemicalmarkers, among others. The sensor circuit may include one or moresub-circuits to digitize, filter, or perform other signal conditioningoperations on the received physiological signal.

In some examples, the physiological signals may be stored in a datastorage device, such as an electronic medical record (EMR) system. Thereceiver circuit 210 may receive a physiological signal from the datastorage device in response to a data retrieval command such as from asystem user.

The receiver circuit 210 may also receive patient medical record from asystem user, or retrieve the information from the EMR system. Thepatient medical record may include patient medical history and treatmentreceived, or other contextual information such as time of day,circumstance or daily life contexts, patient environment, economicsituation, medical care facilities, or caretaker responsibilities. Thepatient medical record may also include patient demographic information,such as age, race, gender, cigarette smoking, hypertension, diabetes, orobesity, among others. The patient medical record may be used by thepatient management system 200 to detect a target physiological andtitrate therapy such as medication dosage.

The physiological event detector circuit 220 may be configured to detecta target physiological event, such as worsening heart failure (WHF). Inan example, the physiological event detector circuit 220 can beimplemented as a part of a microprocessor circuit in the patientmanagement system 100. The microprocessor circuit can be a dedicatedprocessor such as a digital signal processor, application specificintegrated circuit (ASIC), microprocessor, or other type of processorfor processing information including heart sounds. Alternatively, themicroprocessor circuit can be a general-purpose processor that canreceive and execute a set of instructions of performing the functions,methods, or techniques described herein.

In an example such as illustrated in FIG. 2 , the physiological eventdetector circuit 220 may include circuit sets comprising one or more ofa signal metric generator circuit 222, a trending circuit 224, and adetector circuit 226. These circuits, alone or in combination, performthe functions, methods, or techniques described herein. In an example,hardware of the circuit set may be immutably designed to carry out aspecific operation (e.g., hardwired). In an example, the hardware of thecircuit set may include variably connected physical components (e.g.,execution units, transistors, simple circuits, etc.) including acomputer readable medium physically modified (e.g., magnetically,electrically, moveable placement of invariant massed particles, etc.) toencode instructions of the specific operation. In connecting thephysical components, the underlying electrical properties of a hardwareconstituent are changed, for example, from an insulator to a conductoror vice versa. The instructions enable embedded hardware (e.g., theexecution units or a loading mechanism) to create members of the circuitset in hardware via the variable connections to carry out portions ofthe specific operation when in operation. Accordingly, the computerreadable medium is communicatively coupled to the other components ofthe circuit set member when the device is operating. In an example, anyof the physical components may be used in more than one member of morethan one circuit set. For example, under operation, execution units maybe used in a first circuit of a first circuit set at one point in timeand reused by a second circuit in the first circuit set, or by a thirdcircuit in a second circuit set at a different time.

The signal metric generator circuit 222 may generate a signal metricusing one or more received physiological signals. The signal metric mayinclude statistical parameters extracted from the sensed physiologicalsignal, such as signal mean, median, or other central tendency measuresor a histogram of the signal intensity, among others. In some examples,the signal metric may include morphological parameters extracted fromthe sensed physiological signal, such as maximum or minimum within aspecified time period such as a cardiac cycle, positive or negativeslope or higher order statistics, signal power spectral density at aspecified frequency range, among other morphological parameters.Depending on the types of the sensed physiological signal, examples ofthe signal metrics may include thoracic impedance magnitude, intensityof a heart sound component including first (S1), second (S2), third (S3)or fourth (S4), a ratio of a S3 heart sound intensity to a referenceheart sound intensity (such as S1 heart sound intensity, heart soundsignal energy between R-wave and S2, or heart sound signal energy withina cardiac cycle), a thoracic impedance, a respiration rate, a tidalvolume, a ratio a respiration rate to a tidal volume, an activityintensity, or a time duration when the activity intensity is within aspecified range or above a specified threshold, among others. In someexamples, the signal metrics may include timing parameters, such as oneor more HS-based cardiac timing intervals (CTI). The CTI representselectromechanical coupling of the heart, and can be indicative ofcardiac functionality and hemodynamic status. Examples of the CTI mayinclude a pre-ejection period (PEP) such as measured between the onsetof the QRS to the S1 heart sound, a systolic timing interval (STI) suchas measured between the onset of the QRS complex on the ECG to the S2heart sound, a left-ventricular ejection time (LVET) such as measured asan interval between S1 and S2 heart sounds, or a diastolic timinginterval (DTI) such as measured between the S2 heart sound and the onsetof the subsequent QRS complex on the ECG, among others. In someexamples, the HS metric generator circuit 222 may generate compositemeasures such as PEP/LVET ratio, STI/DTI ratio, STI/ cycle length (CL)ratio, or DTI/CL ratio, among others.

The trending circuit 224 may trend the signal metric over time. Thesignal metric trend may be formed using multiple measurements of thesignal metric during a specified period of time. In an example, thesignal metric trend may include a daily trend including dailymeasurements of a signal metric over a specified number of days. Thedaily measurement may be determined as a central tendency of a pluralityof measurements obtained within a day. In an example, a HS metric may betrended over multiple cardiac cycles or over a period of time. Inanother example, a thoracic impedance trend may be generated usingportions of the received impedance signal during identical phases of acardiac cycle such as within a certain time window relative to R-wave ina ECG signal), or at identical phases of a respiratory cycle such aswithin an inspiration phase or an expiration phase of a respirationsignal. This may minimize or attenuate the interferences such as due tocardiac or respiratory activities, in the impedance measurements. Thethoracic impedance trend may be generated using impedance measurementscollected during one or more impedance acquisition and analysissessions. In an example, an impedance acquisition and analysis sessionmay start between approximately 5 a.m. and 9 a.m. in the morning, andlasts for approximately 2-8 hours. In another example, the impedanceacquisition and analysis session may be programmed to exclude certaintime periods, such as night time, or when the patient is asleep. Theimpedance parameter may be determined as a median of multiple impedancemeasurements acquired during the impedance acquisition and analysissession.

The detector circuit 226 may detect a target physiological event usingthe signal metric trend. In an example, the detector circuit 226 may useone or more signal metric trends to detect an event leading to WHF. Thedetector circuit 226 may include a comparator to compare the signalmetric trend to a detection threshold to determine an onset or atermination of a WHF event. For example, a WHF event may be detected ifS3 intensity ||S3||, such as S3 amplitude or signal energy within the S3detection window, exceeds an S3 intensity threshold. A louder S3 such asthe ||S3|| exceeding an S3 intensity threshold may indicate reducedcompliance of the ventricles and deterioration of diastolic function,which may lead to WHF.

In some examples, the signal metric generator 222 may generate acomposite signal metric using a combination of signal metrics. Thetrending circuit 224 may trend the composite signal metric over time,and the detector circuit 226 may detect the target physiological eventwhen the composite signal metric exceeds a detection threshold.

In some examples, the detector circuit 226 may process the signal metricor the composite signal metric to generate a predictor trend indicatingtemporal changes of the signal metric trend. The temporal change may becalculated using a difference between short-term values and baselinevalues. In an example, the short-term values may include statisticalvalues such as a central tendency of the measurements of the signalmetric within a short-term window of a first plurality of days. Thebaseline values may include statistical values such as a centraltendency of the measurements of the signal metric within a long-termwindow of a second plurality of days preceding the short-term window intime. In some examples, the predictor trend may be determined using alinear or nonlinear combination of the relative differences betweenmultiple short-term values corresponding to multiple first time windowsand multiple baseline values corresponding to multiple second timewindows, wherein the differences may be scaled by respective weightfactors which may be based on timing information associated withcorresponding multiple short-term window, such as described by Thakur etal., in U.S. Pat. Publication No. 2017/0095160, entitled “PREDICTIONS OFWORSENING HEART FAILURE”, which is herein incorporated by reference inits entirety.

The therapy control circuit 230 may be coupled to the trending circuit224 and the detector circuit 226, and generate a therapy titrationprotocol 232 using the signal metric trend from the trending circuit 224and the information about the detected physiological event from thedetector circuit 226. The therapy control circuit 230 may dynamicallyup-titrate or down-titrate the therapy dosage in accordance with thegrowth trend or a decay trend of the signal metric or the compositesignal metric. Up-titration of therapy dosage refers to an increase inquantity or frequency of medication dose at specified time or manner, anincrease in electrostimulation intensity or duration at specified timeor manner, or addition of a new medication or device therapy such as toboost therapeutic effect at specified time or manner. Down-titration oftherapy dosage refers to a decrease in quantity or frequency ofmedication dose at specified time or manner, a decrease inelectrostimulation intensity or duration at specified time or manner, orcutback of a present medication or device therapy at specified time ormanner. Timing of the therapy titration may be based on the timing ofonset or termination of the detected physiological event. In someexamples, up- or down-titration of therapy dosage may be triggered byone or more medical events. For example, a down-titration of diureticmay be initiated if the patient is over diuresis, or an up-titration ofdiuretic may be initiated if the patient undergoes a surgery thatrequires intravenous fluid infusion.

The therapy titration protocol 232 may include a temporal profile oftherapy dosage. The therapy dosage represents individualized quantityand frequency of one or more therapeutic agents (e.g., medications orelectrostimulation) relative to a target dosage. The target dosagerepresents a baseline therapeutic agent dosage administered to patientsof similar medical conditions. The target dosage may be based on safetyand efficacy information about the therapeutic agent, and provided tothe patient management system 200 by a system user such as via the userinterface 240. Examples of therapy titration protocol 232 are discussedbelow, such as with reference to FIGS. 3-5 .

The therapy unit 250 may be configured to deliver a therapy to thepatient according to the therapy titration protocol 232 in response tothe detection of WHF event. In an example, the therapy unit 250 mayinclude an electrostimulator circuit configured to generate and deliverelectrostimulation therapy to treat a medical condition such as WHF inresponse to a detection of an event leading to WHF. Examples of theelectrostimulation may include cardiac pacing therapy, cardioversiontherapy, defibrillation therapy, or electrostimulation of non-cardiactissues such as nerve tissues, muscle tissues, among other excitabletissues of the patient. The therapy control circuit 230 may generate aHF electrostimulation protocol including the stimulation site,stimulation mode, or stimulation timing and stimulation energy, amongother parameters. The stimulation mode may include cardiacresynchronization therapy (CRT), which may be a biventricular (BiV)pacing of both left and right ventricles, or synchronized left ventricle(LV)-only pacing. The stimulation mode may also include single sitepacing of only one site of a heart chamber (e.g., the left ventricle)within a cardiac cycle, or multisite pacing (MSP) of two or more sitesof a heart chamber within the same cardiac cycle. In an example, the MSPmay be delivered within the LV. Two or more LV sites may be selected forpacing via multiple LV electrodes. Stimulation strength parameterscontrols the amount of energy delivered to the pacing site. Examples ofthe stimulation strength parameters may include pulse width, pulseamplitude, frequency, duty cycle, or stimulation duration. Stimulationtiming parameters determine the timing and sequence ofelectrostimulation pulses, and may have an impact on therapy efficacyand hemodynamic outcome. The therapy unit 250 may deliverelectrostimulation according to the electrostimulation protocol, inresponse to the detector circuit 226 detecting the WHF event.

In another example, the therapy unit 250 may include a drug deliverysystem such as a drug infusion pump configured to administer one or moremedication to treat a medical condition such as WHF. Examples of the HFdrug may include diuretics, ACE inhibitors or Angiotensin II receptorblockers, inotropes, or digoxin, among other medications. The therapycontrol circuit 230 may generate a HF therapy titration protocolincluding a temporal profile of HF drug dosage relative to a targetdosage. The therapy unit 250 may automatically, or with clinicianintervention, administer the medication according to the temporalprofile of HF drug dosage, in response to the detector circuit 226detecting the WHF event.

The user interface 240 may include an input unit and an output unit. Inan example, at least a portion of the user interface 240 may beimplemented in the external system 125. The input unit may receive userinput that controls the WHF detection or therapy titration protocolgeneration. In an example, the input unit may receive user input oftarget dosage, which represents a baseline therapeutic agent dosageadministered to patients of similar medical conditions. The user inputmay receive user confirmation, rejection, or otherwise modification oftherapy titration recommendations. The input unit may include an inputdevice such as a keyboard, on-screen keyboard, mouse, trackball,touchpad, touch-screen, or other pointing or navigating devices.

The output unit may include circuitry configured to generate ahuman-perceptible notification of the detected target physiologicalevent. The output circuit may be coupled to a display for displaying thereceived physiological signals, trends of the signal metrics or thecomposite signal metric, the therapy titration protocol, or a therapytitration recommendation, among other intermediate measurements orcomputations. The output circuit 230 may be coupled to a printer forprinting hard copies of information about the event detection andtherapy titration protocol. The information may be presented in a table,a chart, a diagram, or any other types of textual, tabular, or graphicalpresentation formats. The presentation of the output information mayinclude audio or other media format. In an example, the output unit maygenerate alerts, alarms, emergency calls, or other forms of warnings tosignal the system user about the detected target physiological event,such as a WHF event.

Although the discussion of therapy titration protocol throughout thisdocument focuses on the therapy for WHF, this is meant only by way ofexample and not limitation. Systems, devices, and methods discussed inthis document may also be suitable for detecting various sorts ofchronic diseases including, for example, coronary artery disease,chronic obstructive pulmonary disease, or chronic kidney disease, amongmany others.

FIG. 3 illustrates generally an example of a therapy titration system300 configured to generate a therapy titration protocol for treating amedical condition. The therapy titration system 300 is an embodiment ofat least part the patient management system 200. The therapy titrationsystem 300 may include a therapy control circuit 330 coupled to theevent detector 226, the trending circuit 224, and the receiver circuit210 as discussed above with reference to FIG. 2 .

The therapy control circuit 330, which is an embodiment of the therapycontrol circuit 230, may be implemented as a part of a microprocessorcircuit, which may be a dedicated processor or a general-purposeprocessor that may receive and execute a set of instructions ofperforming the functions, methods, or techniques described herein.Alternatively, the therapy control circuit 330 may include circuit setscomprising one or more other circuits or sub-circuits, such as atitration timing circuit 332, an up/down titration circuit 334, a targetdosage adjustment circuit 336, and a therapy titration protocolgenerator 338. These circuits may, alone or in combination, perform thefunctions, methods, or techniques described herein.

The titration timing circuit 332 may be coupled to the event detector226 and the trending circuit 224, and determine timings of dosagetitration using one or more of information about the detection of thephysiological events provided by the event detector 226, or a signalmetric trend or a trend of a composite signal metric provided by thetrending circuit 224. The timings of the dosage titration may includebeginning and end of up-titration, or beginning and end ofdown-titration of a therapy dosage. For example, the therapy controlcircuit 330 may up-titrate the therapy dosage when the signal metrictrend exceeds an onset threshold, indicating an onset of a targetphysiological event. The therapy control circuit 330 may down-titratethe therapy dosage at the time when the signal metric trend falls belowa reset threshold, indicating an end of the detected targetphysiological event. The onset threshold may be the same as or differentfrom the reset threshold. In some examples, the titration timing circuit332 may initiate delayed up-titration of therapy dosage at a latencysubsequent to the signal metric trend crossing the onset threshold.Similarly, the titration timing circuit 332 may initiate delayeddown-titration of therapy dosage at a latency subsequent to the signalmetric trend crossing the reset threshold. The delayed titration mayhelp avoid therapy titration inappropriately triggered by temporaryfluctuation of the signal metric trend, which does not represent asustained worsening or improvement of the underlying condition. In anexample, the therapy control circuit 330 may up-titrate the therapydosage when the signal metric trend exceeds the detection threshold andmaintains a growth trend above the onset threshold. In another example,the therapy control circuit 330 may down-titrate the therapy dosage whenthe signal metric trend indicates lack of a sustained worsening of thephysiological condition, such as when then signal metric trend fallsbelow a detection threshold and maintains a decay trend below the resetthreshold.

The up/down titration circuit 334 may be coupled to the trending circuit224, and determine one or more of a direction of titration (e.g.,up-titration or down-titration), amount of titration, or a mode oftitration of therapy dosage. The amount of titration refers to a changein quantify or in frequency of drug administration or electrostimulationenergy relative a target dosage. The up/down titration circuit 334 mayconfine the up- and down-titration within a bounded range in referenceto the target dosage. For example, the up-titration of the therapydosage may be no higher than a specific upper bound dosage, and thedown-titration of the therapy dosage may be no lower than the targetdosage. The mode of titration refers to a rate of change of therapydosage, or a temporal profile of the change of therapy dosage. Examplesof the titration mode may include linear, piece-wise linear, step,exponential, parabolic, or other non-linear functions. Examples oftitration of therapy dosage, including timing, direction, amount, ormode of titration, are discussed below, such as with reference to FIGS.4A-B.

The target dosage adjustment circuit 336 may be coupled to the receivercircuit 210 and the trending circuit 224, and adjust the target dosageperiodically, or in response to a trigger event or user command. In anexample, the target dosage may adjusted when the signal metric trendsatisfies a specific condition. The receiver circuit 210 may receive,such as from a clinician, a target dosage representing a baselinetherapeutic agent dosage administered to patients of similar medicalconditions. The target dosage adjustment circuit 336 may adjust thetarget dosage using a comparison of the portion of the temporal profileof therapy dosage representing and historical therapy dosage applied tothe patient (such as provided by the therapy titration protocolgenerator 338) to the present target dosage. Unlike the up/downtitration of the therapy dosage that determines instantaneous orshort-term therapy dose, the target dosage adjustment may provide anindividualized long-term reference dosage that may be used to guide theup- or down-titration strategy.

The target dosage adjustment circuit 336 may include a timer circuit todetermine a time duration when the target dosage satisfies a specificcondition relative to the target dosage. In an example, if the temporalprofile of therapy dosage is above the target dosage for a specifiedtime period, which may indicate that the patient is effectively treatedby, and consistently tolerated to, a higher dose above the targetdosage, then the target dosage adjustment circuit 336 may increase thetarget dosage. The target dosage may be increased to a level based onthe temporal profile of therapy dosage during the specified time period.In an example, the target dosage may be increased to a levelcorresponding to a lowest therapy dosage achieved during the specifiedperiod.

In another example, the target dosage adjustment circuit 336 maydecrease the target dosage through a testing procedure. The testingprocedure may involve temporary down-titration of the therapy dosage toa sub-target level that is lower than the present target dosage. Patientresponse to the therapy with the sub-target dosage treatment may beevaluated within an assessment time period. The patient response mayinclude subjective or objective measures, such as patient signs,symptoms, physiological or functional parameters, change of dailyactivities or routines, among others. If the patient experiences noworsening of the physiological or functional conditions during theassessment period, then the target dosage adjustment circuit 336 maydecrease the target dosage to a level corresponding to the down-titratedtherapy dosage. In an example, the patient response may be assessedusing a signal metric trend, or a composite signal metric trend, such asgenerated by the trending circuit 224 from the physiological informationacquired during the testing procedure. The target dosage adjustmentcircuit 336 may decrease the target dosage if the signal metric trendremains within a specific range indicating no worsening of thephysiological condition during the assessment period. Examples of targetdosage adjustment are discussed below, such as with reference to FIGS.5A-B.

The therapy titration protocol generator 338 may generate a therapytitration protocol that defines a set of instructions to assist aclinician or guide a therapy unit in adjusting patient therapy underspecific conditions. As illustrated in FIG. 3 , the titration protocolmay be generated using one or more titration parameters, such astitration timing determined by the titration timing circuit332,titration direction and amount or mode of titration determined bythe up/down titration circuit 334, and the target dosage determined bythe target dosage adjustment circuit 336. The therapy titration protocolmay include a temporal profile of therapy dosage indicating therapydosage at different time. The generated therapy titration protocol maybe presented to a user such as a clinician via a display of the userinterface 240, or be used to guide therapy delivery such as via thetherapy unit 250. Portions of the generated therapy titration protocolmay be used to adjust the target dosage by the target dosage adjustmentcircuit 336.

FIGS. 4A-B illustrate examples of a therapy titration protocoldetermined using a signal metric trend and a target dosage. The therapytitration protocol may be determined using the therapy control circuit230 or the therapy control circuit 330. The therapy titration protocolincludes a set of instructions for adjusting patient therapy underspecific conditions. A temporal profile of therapy dosage may begenerated from the set of instructions. The temporal profile of therapydosage represents individualized quantity and frequency of one or moretherapeutic agents relative to the target dosage.

FIG. 4A illustrates an example of a therapy dosage profile 430 includinga portion of dosage up-titration. The up-titration corresponds in timeto temporal changes of a signal metric trend 410, which may be generatedby the signal metric generator 222 and the trending circuit 224 from oneor more physiological signals. As illustrated in FIG. 4A, the therapydosage starts at a level corresponding to the target dosage 440. As thesignal metric trend 410 ramps up over time and crosses an onsetthreshold 420 at 412, the detector circuit 226 detects an onset ofphysiological event (e.g., a WHF event). Thereafter, the onset threshold420 is decreased to a reset threshold for detecting a termination of thedetected event.

In response to the detection at 412, an up-titration of therapy dosageis initiated. In some examples, the up-titration of therapy dosage maybe delayed until after a specific latency period following the detectionat 412. The up-titration continues as long as the signal metric trend410 maintains a growth trend until it reaches a peak 414. By way ofexample and not limitation, corresponding to the growth trend of thesignal metric trend between 412 and 414, the up-titration may follow astep function. The amount of up-titration or the time interval at eachstep may be constant or variable across the steps, or may be userprogrammable. In an example, the time interval at each step is aconstant, such as one week, or a specified number of days. Following thepeak 414, the signal metric trend 410 decreases. Accordingly, thestep-wise up-titration process stops, and the therapy dosage ismaintained at its present level. Because the signal metric trend 410 isstill above the detection threshold 420 (that is, the detected event hasnot terminated), no down-titration process is initiated in this example.

FIG. 4B illustrates an example of therapy dosage profile 470 including aportion of dosage down-titration. The dosage down-titration correspondsto temporal changes of a signal metric trend 450, which may be generatedby the signal metric generator 222 and the trending circuit 224 from oneor more physiological signals. As illustrated in FIG. 4B, the signalmetric trend 450 begins at a level above a detection threshold 460,indicating an on-going physiological event (e.g., WHF). Correspondingly,the therapy dosage begins at a level higher than the target dosage 480.As the signal metric trend 450 ramps down over time and crosses thedetection threshold 460 at 452, the detector circuit 226 may detect atermination of the physiological event. The therapy dosage, however, maybe maintained for a latency period (T). The latency period (T) may beuser programmable, or determined based on the signal metric trend 450crosses a threshold lower than the detection threshold 460. After thelatency period T, down-titration may be initiated at 454 such as via thetitration timing circuit 332. The delayed down-titration, as illustratedin FIG. 4B, may be beneficial in circumstances where the detection ofphysiological event termination (e.g., detection threshold crossing) isfollowed by fluctuations of the signal metric trend, which may notrepresent a steady decrease of the signal metric trend and a patientcondition under control. Maintaining the therapy dosage for an extendedtime period (e.g., T) may ensure sufficient therapy prior toestablishing a high confidence that the patient condition is undercontrol or has improved over time, at which point a therapydown-titration may be initiated. By way of example and not limitation,corresponding to the decay trend of the signal metric trend 450 between452 and 454, and the sustained low signal metric level beyond 454, thedown-titration may follow a step function. The step-wise down-titrationmay have a constant or variable amount of down-titration and timeinterval at each step. The down-titration continues until the therapydosage reaches the target dosage. The therapy dosage may be maintainedat the target dosage level until the signal metric trend 450 ramps upand exceeds the detection threshold at 456, at which the detectorcircuit 226 may detect an onset of another physiological event. Inresponse to the event detection at 456, the therapy dosage may beincreased from its present level (corresponding to the target dosage) toa specific elevated dosage. Alternatively, the therapy dosage may followa step-wise up-titration similar to the therapy dosage profile 430 inFIG. 4A.

FIGS. 5A-B illustrate examples of target dosage adjustment using acomparison of a temporal profile of therapy dosage and a target dosage.The adjusted target dosage may be generated using the target dosageadjustment circuit 336 as illustrated in FIG. 3 .

FIG. 5A illustrates an example of target dosage profile 540 thatincludes an increase in the target dosage. Also illustrated in FIG. 5Ais a signal metric trend 510 and a therapy dosage profile 530 thatincludes portions of up-titration and down-titration of therapy dosagecorresponding in time to the signal metric trend 510 and the detectionof the onset and the termination of the physiological event, similar tothe previous discussion with reference to FIG. 4A. As illustrated inFIG. 5A, the portions of growth trends of the signal metric trend 510and the threshold crossings at 512 and 514 each may trigger respectiveup-titrations 532 and 534 of the therapy dosage. The portions of decaytrends of the signal metric trend 510 and the threshold crossings at 513and 515 each may trigger respective delayed down-titrations 533 and 535of the therapy dosage following respective latency periods after thethreshold crossings at 513 and 515.

The dosage adjustment circuit 336 may monitor the therapy dosage 530,compare it to the target dosage 540, and count time elapsed when thetarget dosage satisfies a specific condition, such as being above thetarget dosage. In the example illustrated in FIG. 5A, the up-titrationat 532 results in a therapy dosage above the target dosage. Following adecay trend from 513 and a brief period of meandering at a low signalmetric level, the signal metric trend 510 bounces back and demonstratesa growth trend. Corresponding to such a pattern of the signal metrictrend, the down-titration at 533 does not sustain long enough, and thesignal metric trend remains at the level 536 above the target dosage.From the up-titration at 532, the time elapsed (T1) when the therapydosage stays above the target dosage exceeds a duration threshold, andthe target dosage adjustment circuit 336 may increase the target dosageat 542 to a level based on the temporal profile of therapy dosage duringthe specified time period. In an example, the target dosage may beincreased to a level 546 corresponding to a lowest therapy dosage 536achieved during the time period T1. From that point on, therapy dosagetitration may be determined using the signal metric trend 510 and thenew, increased target dosage unless further adjustment of target dosageis initiated.

FIG. 5B illustrates an example of target dosage profile 580 thatincludes a decrease in the target dosage. Also illustrated in FIG. 5B isa signal metric trend 550, and a therapy dosage profile 570 that startsat a level corresponding to a target dosage 580. In FIG. 5B, the signalmetric trend 550 is below the threshold 560 for a prolonged time period,during which the therapy dosage maintains at the target dosage 580.Patient physiological and functional responses may be monitored whilethe patient receives treatment with the target dosage. If no worseningof the physiological or functional condition is indicated for asustained period of time, a testing procedure may be triggered at 572 totemporarily down-titrate the therapy dosage. The amount ofdown-titration may be user programmable. Evaluation of patientphysiological or functional responses to the temporarily down-titratedtherapy dosage may be continued over a time period T2. In some examples,patient physiological or functional responses may be evaluated using thesignal metric or the composite signal metric acquired during thedown-titrated therapy procedure. If the patient demonstrates noworsening of the physiological or functional conditions during theassessment period, or if the signal metric trend 550 remains within aspecific range indicating patient tolerance and therapy efficacy duringthe assessment period, then at 582, the target dosage may be decreasedto a level corresponding to the down-titrated therapy dosage. From thatpoint on, therapy dosage titration may be determined using the signalmetric trend 550 and the new, decreased target dosage unless furtheradjustment of target dosage is initiated.

FIG. 6 illustrates generally an example of a method 600 for adjusting atherapy in a patient using a medical system. The method 600 may beimplemented and executed in an ambulatory medical device such as animplantable or wearable medical device, or in a remote patientmanagement system. In an example, the method 600 may be implemented in,and executed by, the AMD 110, one or more devices in the external system125, or the patient management system 200 or the therapy titrationsystem 300.

The method 600 begins at 610, where one or more physiological signalsmay be received, such as via receiver circuit 210. The physiologicalsignals may be sensed from a patient via one or more implantable,wearable, or otherwise ambulatory sensors or electrodes associated withthe patient. Alternatively, the physiological signals may be receivedfrom a data storage device in response to a data retrieval command suchas from a system user. Examples of the physiological signals may includeECG, intracardiac EGM, thoracic or cardiac impedance signal, arterialpressure signal or cardiac pressure signal, coronary blood temperaturesignal, blood oxygen saturation signal, heart sound signal such assensed by an ambulatory accelerometer or acoustic sensors, physiologicalresponse to activity, apnea hypopnea index, one or more respirationsignals such as a respiration rate signal or a tidal volume signal,brain natriuretic peptide (BNP), blood panel, sodium and potassiumlevels, glucose level and other biomarkers and bio-chemical markers,among others.

At 620, a signal metric from the sensed one or more physiologicalsignals, such as via the signal metric generator circuit 222. The signalmetric may include statistical parameters, morphological parameters, ortiming parameters, among others. In some examples, the signal metric mayinclude a composite signal metric using a combination of signal metrics.The signal metric may be trended over time, such as by using thetrending circuit 224. In an example, the signal metric trend may includea daily trend including daily measurements of a signal metric over aspecified number of days. The daily measurement may be determined as acentral tendency of a plurality of measurements obtained within a day.

At 630, a target physiological event may be detected using the signalmetric trend, such as via the detector circuit 226. An example of thetarget physiological event is an event leading to worsening heartfailure (WHF), such as a heart failure decompensation event. The signalmetric trend, or the composite signal metric trend, may be compared to adetection threshold to determine an onset or a termination of a WHFevent. In an example, a WHF event may be detected if S3 intensity||S3||, such as S3 amplitude or signal energy within the S3 detectionwindow, exceeds an S3 intensity threshold. A louder S3 such as the||S3|| exceeding an S3 intensity threshold may indicate reducedcompliance of the ventricles and deterioration of diastolic function,which may lead to WHF. In some examples, a predictor trend indicatingtemporal changes of the signal metric trend may be calculated using adifference between short-term values and baseline values of a signalmetric or a composite signal metric. The baseline values may includestatistical values such as a central tendency of the measurements of thesignal metric within a long-term window preceding a short-term windowfrom which the short-term values are computed. A WHF event is detectedif the predictor trend exceeds a threshold.

At 640, a therapy titration protocol may be generated using the signalmetric trend and the information about the detected physiological event,such as via the therapy control circuit 230. The therapy titrationprotocol may include a temporal profile of therapy dosage. The temporalprofile of therapy dosage may include one or more of an up-titration ora down-titration of therapy dosage corresponding to the growth trend ora decay trend of the signal metric or the composite signal metric.Up-titration of therapy dosage refers to an increase in quantity orfrequency of medication dose at specified time or manner, or an increasein electrostimulation intensity or duration at specified time or manner.Down-titration of therapy dosage refers to a decrease in quantity orfrequency of medication dose at specified time or manner, or a decreasein electrostimulation intensity or duration at specified time or manner.Timing of the therapy titration may be based on the timing of onset ortermination of the detected physiological event. Examples of methods fortitrating therapy are discussed below, such as with reference to FIG. 7.

The therapy dosage represents individualized quantity and frequency ofone or more therapeutic agents relative to a target dosage. The targetdosage represents baseline therapeutic agent dosage administered topatients of similar medical conditions. The target dosage may be basedon safety and efficacy information about the therapeutic agent. Unlikethe up/down titration of the therapy dosage which determinesinstantaneous or short-term therapy dose, the target dosage adjustmentmay provide an individualized long-term reference dosage, and may beused to guide the up- or down-titration strategy. The target dosage maybe adjusted based on patient response. Examples of methods of adjustingtarget dosage are discussed below, such as with reference to FIG. 7 .

The therapy titration protocol may be output to a user (e.g., aclinician) or a process at 652, such as being displayed on a display ofthe user interface 240. The received physiological signals, trends ofthe signal metrics or the composite signal metric, or therapy titrationrecommendations, among other intermediate measurements or computations,may also be displayed. Additionally or alternatively, at 654, therapiesmay be delivered according to the therapy titration protocol, such asvia the therapy circuit 260. Examples of the therapy may includeelectrostimulation therapy delivered to the heart, a nerve tissue, othertarget tissues, a cardioversion therapy, a defibrillation therapy, ordrug therapy including delivering drug to a tissue or organ.Electrostimulation therapy may be delivered according to a HF therapytitration protocol that specifies stimulation site, stimulation mode, orstimulation timing and stimulation energy, among other parameters. Insome examples, at 654, the therapy may include drug therapy, such asdelivered via a drug infusion pump to treat WHF. Examples of the HF drugmay include diuretics, ACE inhibitors or Angiotensin II receptorblockers, inotropes, or digoxin, among other medications. Medication maybe automatically, or with a clinician intervention, administeredaccording to the temporal profile of HF drug dosage, in response to thedetected WHF event.

FIG. 7 illustrates generally an example of a method 700 for generating atherapy dosage profile that may be used to guide treatment of a medicalcondition such as WHF. The method 700 may be an embodiment of a portionof the method 600, such as step 640 of generating a therapy titrationprotocol. The method 700 may be implemented in, and executed by thetherapy titration system 300, and include a set of instructions foradjusting patient therapy under specific conditions.

The method 700 begins at 710 to compare the signal metric trend or thecomposite signal metric trend generated 620 to one or more detectionthresholds, such as a WHF onset threshold TH₁ or a WHF reset thresholdTH₂. By way of example and not limitation, an increase trend of thesignal metric indicates sustained worsening of heart failure status, anda decrease trend of the signal metric indicates lack of sustainedworsening of heart failure status (e.g., a heart failure status that isunder control or has improved over time). A beginning of the WHF eventis detected when the signal metric trend increases and exceeds the onsetthreshold TH₁. An end of the detected WHF event is detected when thesignal metric trend decreases and falls below the reset threshold TH₂.The onset threshold TH₁ may be the same as, or different from, the resetthreshold TH₂.

The threshold crossing may trigger the dosage titration, such as via thetitration timing circuit 332. At 720, if the signal metric trend exceedsTH₁, and if the signal metric maintains a growth trend above thedetection threshold TH₁, then an up-titration of therapy dosage may becarried out at 741 to alleviate the worsening of heart failure. If nothreshold crossing of TH₁ is detected, the signal metric trend may becompared to the reset threshold TH₂. At 730, if the signal metric trendfalls below the reset threshold TH₂, and if the signal metric maintainsa decay trend below the detection threshold TH₂, then a down-titrationof therapy dosage may be performed at 742 to adapt to the heart failurestatus that is under control or has improved over time with the presenttherapy. If no threshold crossing of TH₁ or TH₂ is detected, or if thethreshold crossing of TH₁ is not accompanied by a maintained growthtrend, or if the threshold crossing of TH₂ is not accompanied by amaintained decay trend, then at 743, the therapy dosage may bemaintained at its present level without titration.

In some examples, the up-titration of therapy dosage at 741 or thedown-titration of therapy dosage at 742 may be initiated at a latencyafter the signal metric trend crosses the respective onset threshold TH₁or the reset threshold TH₂. Such delayed titration may be beneficial incircumstances where the detection of physiological event termination(e.g., detection threshold crossing) is followed by fluctuations of thesignal metric trend. Maintaining the therapy dosage for an extended timeperiod may ensure sufficient therapy prior to establishing a highconfidence that the patient condition is under control or has improvedover time with the present therapy, at which point the down-titration oftherapy may be initiated.

The up-titration at 741 and the down-titration 742 of therapy dosage maybe confined within a bounded range with respect to a target dosage. Forexample, the up-titration of the therapy dosage is no higher than aspecific upper bound dosage, or the down-titration of the therapy dosageis no lower than the target dosage. The amount of up- or down-titrationcorresponds to a change in quantify or in frequency of drugadministration or electrostimulation energy relative a target dosage. Asillustrated in FIG. 7 , the method 700 includes a method 750 forautomatic adjustment of the target dosage. The method 750 may beimplemented in, and executed by, the target dosage adjustment circuit336. The therapy dosage profile, including historical dosage, may becompared to the present target dosage at 751. If it is determined at 752that the therapy dosage is above the present target dosage for at leasta sustained time period of T1, then the patient is effectively treatedby, and consistently tolerated to, the higher dose above the targetdosage. Accordingly, at 753, the target dosage may be increased to alevel based on the temporal profile of therapy dosage during thespecified time period. In an example, the target dosage may be increasedto a level corresponding to a lowest therapy dosage achieved during thespecified period, such as the example illustrated in FIG. 5A.

At 754, if it is determined that the therapy dosage maintains at thepresent target dosage for a prolonged time period, such as approximately60-120 days, then a testing procedure may be initiated at 755 to attemptto decrease the target dosage. The testing procedure may involvetemporary down-titrating the therapy dosage to a level lower than thepresent target dosage, such as the example illustrated in FIG. 5B. At756, patient response to the therapy with the sub-target dosagetreatment may be evaluated within an assessment time period T2. Thepatient response may be assessed using subjective or objective measures,such as patient signs, symptoms, physiological or functional parameters,change of daily activities or routines, among others. If at 757 thepatient demonstrates no worsening of the physiological or functionalconditions during the assessment period T2, or if the signal metrictrend remains within a specific range indicating patient tolerance andtherapy efficacy during the assessment period T2, then at 758 the targetdosage may be decreased to a level corresponding to the down-titratedtherapy dosage. If at 757 the patient demonstrates worsening of thephysiological or functional conditions during the assessment period T2,then the target dosage is maintained at its present level, and thetarget dosage assessment may continue at 751.

The adjusted target dosage, such as an increase of the target dosage asdetermined at 753, or the decrease of the target dosage as determined at758, may be used to determine the amount of therapy dosage up-titrationat 741 and the therapy dosage down-titration at 742. The up- ordown-titration of therapy dosage may follow a specified titration modethat indicates a rate of change of therapy dosage, or a temporal profileof the change of therapy dosage. By way of example and not limitation,FIGS. 4A-B illustrated step-wise up-titration and step-wisedown-titration modes. Other examples of the titration mode may includelinear, piece-wise linear, exponential, parabolic, or other non-linearfunctions.

At 760, a therapy dosage profile may be generated using the therapytitrations at 741 and 742 or the maintained therapy dosage at 743 atdifferent time. The therapy dosage profile, which is a part of thetherapy titration protocol, may be presented to a user such as aclinician at 652, or to be used to guide therapy delivery at 654.

FIG. 8 illustrates generally a block diagram of an example machine 800upon which any one or more of the techniques (e.g., methodologies)discussed herein may perform. Portions of this description may apply tothe computing framework of various portions of the LCP device, the IMD,or the external programmer.

In alternative embodiments, the machine 800 may operate as a standalonedevice or may be connected (e.g., networked) to other machines. In anetworked deployment, the machine 800 may operate in the capacity of aserver machine, a client machine, or both in server-client networkenvironments. In an example, the machine 800 may act as a peer machinein peer-to-peer (P2P) (or other distributed) network environment. Themachine 800 may be a personal computer (PC), a tablet PC, a set-top box(STB), a personal digital assistant (PDA), a mobile telephone, a webappliance, a network router, switch or bridge, or any machine capable ofexecuting instructions (sequential or otherwise) that specify actions tobe taken by that machine. Further, while only a single machine isillustrated, the term “machine” shall also be taken to include anycollection of machines that individually or jointly execute a set (ormultiple sets) of instructions to perform any one or more of themethodologies discussed herein, such as cloud computing, software as aservice (SaaS), other computer cluster configurations.

Examples, as described herein, may include, or may operate by, logic ora number of components, or mechanisms. Circuit sets are a collection ofcircuits implemented in tangible entities that include hardware (e.g.,simple circuits, gates, logic, etc.). Circuit set membership may beflexible over time and underlying hardware variability. Circuit setsinclude members that may, alone or in combination, perform specifiedoperations when operating. In an example, hardware of the circuit setmay be immutably designed to carry out a specific operation (e.g.,hardwired). In an example, the hardware of the circuit set may includevariably connected physical components (e.g., execution units,transistors, simple circuits, etc.) including a computer readable mediumphysically modified (e.g., magnetically, electrically, moveableplacement of invariant massed particles, etc.) to encode instructions ofthe specific operation. In connecting the physical components, theunderlying electrical properties of a hardware constituent are changed,for example, from an insulator to a conductor or vice versa. Theinstructions enable embedded hardware (e.g., the execution units or aloading mechanism) to create members of the circuit set in hardware viathe variable connections to carry out portions of the specific operationwhen in operation. Accordingly, the computer readable medium iscommunicatively coupled to the other components of the circuit setmember when the device is operating. In an example, any of the physicalcomponents may be used in more than one member of more than one circuitset. For example, under operation, execution units may be used in afirst circuit of a first circuit set at one point in time and reused bya second circuit in the first circuit set, or by a third circuit in asecond circuit set at a different time.

Machine (e.g., computer system) 800 may include a hardware processor 802(e.g., a central processing unit (CPU), a graphics processing unit(GPU), a hardware processor core, or any combination thereof), a mainmemory 804 and a static memory 806, some or all of which may communicatewith each other via an interlink (e.g., bus) 808. The machine 800 mayfurther include a display unit 810 (e.g., a raster display, vectordisplay, holographic display, etc.), an alphanumeric input device 812(e.g., a keyboard), and a user interface (UI) navigation device 814(e.g., a mouse). In an example, the display unit 810, input device 812and UI navigation device 814 may be a touch screen display. The machine800 may additionally include a storage device (e.g., drive unit) 816, asignal generation device 818 (e.g., a speaker), a network interfacedevice 820, and one or more sensors 821, such as a global positioningsystem (GPS) sensor, compass, accelerometer, or other sensor. Themachine 800 may include an output controller 828, such as a serial(e.g., universal serial bus (USB), parallel, or other wired or wireless(e.g., infrared (IR), near field communication (NFC), etc.) connectionto communicate or control one or more peripheral devices (e.g., aprinter, card reader, etc.).

The storage device 816 may include a machine readable medium 822 onwhich is stored one or more sets of data structures or instructions 824(e.g., software) embodying or utilized by any one or more of thetechniques or functions described herein. The instructions 824 may alsoreside, completely or at least partially, within the main memory 804,within static memory 806, or within the hardware processor 802 duringexecution thereof by the machine 800. In an example, one or anycombination of the hardware processor 802, the main memory 804, thestatic memory 806, or the storage device 816 may constitute machinereadable media.

While the machine-readable medium 822 is illustrated as a single medium,the term “machine readable medium” may include a single medium ormultiple media (e.g., a centralized or distributed database, and/orassociated caches and servers) configured to store the one or moreinstructions 824.

The term “machine readable medium” may include any medium that iscapable of storing, encoding, or carrying instructions for execution bythe machine 800 and that cause the machine 800 to perform any one ormore of the techniques of the present disclosure, or that is capable ofstoring, encoding or carrying data structures used by or associated withsuch instructions. Non-limiting machine-readable medium examples mayinclude solid-state memories, and optical and magnetic media. In anexample, a massed machine-readable medium comprises a machine readablemedium with a plurality of particles having invariant (e.g., rest) mass.Accordingly, massed machine-readable media are not transitorypropagating signals. Specific examples of massed machine-readable mediamay include: non-volatile memory, such as semiconductor memory devices(e.g., Electrically Programmable Read-Only Memory (EPROM), ElectricallyErasable Programmable Read-Only Memory (EPSOM)) and flash memorydevices; magnetic disks, such as internal hard disks and removabledisks; magneto-optical disks; and CD-ROM and DVD-ROM disks.

The instructions 824 may further be transmitted or received over acommunication network 826 using a transmission medium via the networkinterface device 820 utilizing any one of a number of transfer protocols(e.g., frame relay, internet protocol (IP), transmission controlprotocol (TCP), user datagram protocol (UDP), hypertext transferprotocol (HTTP), etc.). Example communication networks may include alocal area network (LAN), a wide area network (WAN), a packet datanetwork (e.g., the Internet), mobile telephone networks (e.g., cellularnetworks), Plain Old Telephone (POTS) networks, and wireless datanetworks (e.g., Institute of Electrical and Electronics Engineers (IEEE)802.11 family of standards known as WiFi®, IEEE 802.16 family ofstandards known as WiMax®), IEEE 802.15.4 family of standards,peer-to-peer (P2P) networks, among others. In an example, the networkinterface device 820 may include one or more physical jacks (e.g.,Ethernet, coaxial, or phone jacks) or one or more antennas to connect tothe communication network 826. In an example, the network interfacedevice 820 may include a plurality of antennas to wirelessly communicateusing at least one of single-input multiple-output (SIMO),multiple-input multiple-output (MIMO), or multiple-input single-output(MISO) techniques. The term “transmission medium” shall be taken toinclude any intangible medium that is capable of storing, encoding orcarrying instructions for execution by the machine 800, and includesdigital or analog communications signals or other intangible medium tofacilitate communication of such software.

Various embodiments are illustrated in the figures above. One or morefeatures from one or more of these embodiments may be combined to formother embodiments.

The method examples described herein can be machine orcomputer-implemented at least in part. Some examples may include acomputer-readable medium or machine-readable medium encoded withinstructions operable to configure an electronic device or system toperform methods as described in the above examples. An implementation ofsuch methods may include code, such as microcode, assembly languagecode, a higher-level language code, or the like. Such code may includecomputer readable instructions for performing various methods. The codecan form portions of computer program products. Further, the code can betangibly stored on one or more volatile or non-volatilecomputer-readable media during execution or at other times.

The above detailed description is intended to be illustrative, and notrestrictive. The scope of the disclosure should therefore be determinedwith references to the appended claims, along with the full scope ofequivalents to which such claims are entitled.

What is claimed is:
 1. A system for adjusting a therapy delivered to apatient, the system comprising: a physiological event detector circuitconfigured to: generate a composite signal metric using a plurality ofphysiological signals sensed from the patient; and trend the compositesignal metric over time; and a therapy control circuit configured toadjust a therapy parameter in response to the trended composite signalmetric satisfying a predetermined trend condition.
 2. The system ofclaim 1, wherein the therapy delivered to the patient includes anelectrostimulation therapy, wherein to adjust the therapy parameterincludes to adjust an electrostimulation parameter in response to thetrended composite signal metric satisfying the predetermined trendcondition.
 3. The system of claim 1, wherein the therapy delivered tothe patient includes an drug therapy, wherein to adjust the therapyparameter includes to adjust a drug dosage in response to the trendedcomposite signal metric satisfying the predetermined trend condition. 4.The system of claim 1, wherein the physiological event detector circuitis configured to detect a worsening heart failure (WHF) event using thetrended composite signal metric, wherein the therapy control circuit isconfigured to adjust the therapy parameter further in response to thedetection of the WHF event.
 5. The system of claim 1, wherein thetherapy control circuit is configured to generate a therapy titrationprotocol including values of the therapy parameter varied over timerelative to a target therapy parameter value.
 6. The system of claim 5,wherein the values of the therapy parameter are varied in accordancewith the trended composite signal metric.
 7. The system of claim 6,wherein the therapy titration protocol includes a stepwise change in thevalues of the therapy parameter in accordance with the trended compositesignal metric.
 8. The system of claim 5, wherein the target therapyparameter includes a baseline electrostimulation parameter value for anelectrostimulation therapy, or a baseline drug dosage for a drugtherapy.
 9. The system of claim 5, wherein the therapy control circuitis further configured to, when the values of the therapy parameter areabove the target therapy parameter value for a predetermined timeperiod, increase the target therapy parameter value to a levelcorresponding to a lowest therapy parameter value during thepredetermined time period.
 10. The system of claim 5, wherein thetherapy control circuit is further configured to: evaluate a patientresponse to a therapy delivered over a monitoring time period inaccordance with a lower therapy parameter value than the target therapyparameter value; and change the target therapy parameter value to thelower therapy parameter value if the patient response indicates noworsening of the physiological condition during the monitoring timeperiod.
 11. The system of claim 1, wherein to adjust the therapyparameter, the therapy control circuit is configured to: increase anelectrostimulation energy or a drug dosage in response to the trendedcomposite signal metric indicating an increasing trend; and maintain ordecrease the electrostimulation energy or the drug dosage in response tothe trended composite signal metric indicating a decreasing trend. 12.The system of claim 1, wherein to adjust the therapy parameter, thetherapy control circuit is configured to: increase an electrostimulationenergy or a drug dosage in response to the trended composite signalmetric exceeding a composite signal metric threshold value; and maintainor decrease the electrostimulation energy or the drug dosage in responseto the trended composite signal metric falling below the compositesignal metric threshold value.
 13. A method of adjusting a therapydosage in a patient using a medical system, the method comprising:receiving a plurality of physiological signals sensed from a patient;generating a composite signal metric of the received plurality ofphysiological signals using a physiological event detector circuit;trending the composite signal metric over time using the physiologicalevent detector circuit; and adjusting a therapy parameter in response tothe trended composite signal metric satisfying a predetermined trendcondition.
 14. The method of claim 13, wherein the therapy delivered tothe patient includes an electrostimulation therapy, wherein adjustingthe therapy parameter includes adjusting an electrostimulation parameterin response to the trended composite signal metric satisfying thepredetermined trend condition.
 15. The method of claim 13, wherein thetherapy delivered to the patient includes an drug therapy, whereinadjusting the therapy parameter includes adjusting a drug dosage inresponse to the trended composite signal metric satisfying thepredetermined trend condition.
 16. The method of claim 13, comprisinggenerating a therapy titration protocol including values of the therapyparameter varied over time relative to a target therapy parameter value.17. The method of claim 16, wherein the values of the therapy parameterare varied in accordance with the trended composite signal metric. 18.The method of claim 16, comprising, when the values of the therapyparameter are above the target therapy parameter value for apredetermined time period, increasing the target therapy parameter valueto a level corresponding to a lowest therapy parameter value during thepredetermined time period.
 19. The method of claim 13, wherein adjustingthe therapy parameter includes: increasing an electrostimulation energyor a drug dosage in response to the trended composite signal metricindicating an increasing trend; and maintaining or decreasing theelectrostimulation energy or the drug dosage in response to the trendedcomposite signal metric indicating a decreasing trend.
 20. The method ofclaim 13, wherein adjusting the therapy parameter includes: increasingan electrostimulation energy or a drug dosage in response to the trendedcomposite signal metric exceeding a composite signal metric thresholdvalue; and maintaining or decreasing the electrostimulation energy orthe drug dosage in response to the trended composite signal metricfalling below the composite signal metric threshold value.